Lymphedema occurs with obstruction, destruction, or functional inadequacy of lymph vessels. The resultant accumulation of interstitial fluid, containing high molecular weight proteins and other cellular debris, produces a condition with a complex biology that extends far beyond edema. Lymphedema may be primary or secondary (acquired). Primary lymphedema can be present from birth (congenital lymphedema), may occur during puberty (lymphedema praecox), and less often presents later in life (lymphedema tarda). Acquired lymphedema is a common, important and often devastating consequence of successful surgical and radiotherapy of breast cancer and many other malignancies. It is characterized by the impaired transport and consequent accumulation of interstitial fluid, with accompanying swelling of subcutaneous tissues. Secondary lymphedema can also result from trauma or infection, including dermatophytosis in the foot.
Lymphedema may be complicated by direct infection of the vascular channels (lymphangitis), which is manifested by chills, high fever, toxicity, and a red, hot, swollen extremity. Lymphangitic streaks may be seen in the skin, and the recipient lymph nodes are usually enlarged and tender. These features differentiate lymphangitis from acute thrombophlebitis. Lymphedema patients are also prone to recurrent attacks of soft tissue bacterial infection (cellulites or erysipelas); the accompanying systemic signs of infection are often blunted. These recurrent infections are the source of substantial morbidity and are difficult to prevent or eradicate.
In lymphedema, the lymphatic transport capacity is not sufficient to offset the lymphatic load. This causes the normal volume of interstitial fluid formation to exceed the rate of lymphatic return, resulting in the accumulation of interstitial fluid, enriched by the content of high molecular weight proteins. The result is a high-protein edema, or lymphedema, with protein concentrations of 1.0-5.5 g/mL. The high oncotic pressure in the interstitium favors the continued accumulation of water.
Accumulation of interstitial fluid leads to massive dilatation of the remaining outflow tracts, along with valvular incompetence that causes reversal of flow from subcutaneous tissues into the dermal plexus. A marked inflammatory reaction is initiated. Macrophage activity is increased, resulting in destruction of elastic fibers and production of fibrosclerotic tissue. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic. The result of this inflammatory reaction is a change from the initial pitting edema to the increasingly brawny non-pitting edema characteristic of the later stages of lymphedema. The overlying skin becomes thickened, forming thick scaly deposits of keratinized debris, and may display a warty verrucosis. Cracks and furrows often develop and accommodate debris and bacteria, facilitating soft tissue infection and leading to lymphorrhea, the external leakage of lymph through the skin.
In the United States, the highest incidence of lymphedema is observed following breast cancer surgery, particularly among those who undergo radiation therapy following axillary lymphadenectomy. Among this population, 10-40% develop some degree of ipsilateral upper extremity lymphedema. Worldwide, 90 million cases of lymphedema are estimated to exist, with filariasis being the most common cause. Prevalence estimates of lymphedema, both in the United States and worldwide, are indirect, and likely reflect an underestimation of the burden of disease.
Patients with chronic lymphedema for more than 10 years have a small, but identifiable, risk of developing lymphangiosarcoma. Patients with this tumor commonly present with a reddish purple discoloration or nodule that tends to form satellite lesions. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis because of its propensity for early, aggressive metastasis. Other complications of lymphedema include recurrent bouts of cellulitis and/or lymphangitis, severe functional impairment, and, rarely, the need for amputation. Complications following surgery are common and include partial wound dehiscence, seroma, hematoma, skin necrosis, and exacerbation of foot or hand edema.
Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Many surgical procedures have been advocated. None of the surgical interventions has a clearly documented favorable long-term results.
Improved treatment of lymphedema, both primary and secondary (or acquired), is of great clinical and scientific interest. The present invention addresses this need by providing new methods for treating lymphedema, for reducing the risk of incurring the complications of lymphedema, for preventing or at least slowing the progression of lymphedema, for reversing the fluid accumulation or, in later stages of the disease, tissue architecture changes that accompany disease progression, and for preventing the disease from developing in patients likely to develop it.
Publications of interest, each specifically incorporated by reference, for the artisan contemplating this disclosure may include Mortimer & Rockson The Journal of Clinical Investigation 124, 915-921 (2014); Rockson Lymphatic research and biology 11, 117-120 (2013); Nakamura et al. PloS one 4, e8380 (2009); Tian, W., et al. Science translational medicine 5, 200ra117 (2013); Yoon, C. M., et al. Blood 112, 1129-1138 (2008); Pham, et al. The Journal of experimental medicine 207, 17-27 (2010); Zheng et al. The Journal of clinical investigation 124, 878-887 (2014); Anelli et al. FASEB journal 24, 2727-2738 (2010); Fatima, et al. Developmental dynamics 243, 957-964 (2014); Kunkel, et al. Nature reviews. Drug discovery 12, 688-702 (2013).